Delivery of nonsteroidal antiinflammatory drugs through an inhalation route

ABSTRACT

The present invention relates to the delivery of nonsteroidal antiinflammatory drugs (NSAIDs) through an inhalation route. Specifically, it relates to aerosols containing NSAIDs that are used in inhalation therapy. In a method aspect of the present invention, an NSAID is delivered to a patient through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises an NSAID, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles with less than 5% NSAID degradation products. In a kit aspect of the present invention, a kit for delivering an NSAID through an inhalation route is provided which comprises: a) a thin coating of an NSAID composition and b) a device for dispensing said thin coating as a condensation aerosol.

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/155,097, entitled “Delivery of Nonsteroidal AntiinflammatoryDrugs Through an Inhalation Route,” filed May 23, 2002, Rabinowitz andZaffaroni, which claims priority to U.S. provisional application SerialNo. 60/294,203 entitled “Thermal Vapor Delivery of Drugs,” filed May 24,2001, Rabinowitz and Zaffaroni and to U.S. provisional applicationSerial No. 60/317,479 entitled “Aerosol Drug Delivery,” filed Sep. 5,2001, Rabinowitz and Zaffaroni, the entire disclosures of which arehereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the delivery of nonsteroidalanti-inflammatory drugs (NSAIDs) through an inhalation route.Specifically, it relates to aerosols containing NSAIDs that are used ininhalation therapy.

BACKGROUND OF THE INVENTION

[0003] There are a number of nonsteroidal compositions currentlymarketed for the treatment of inflammation. The compositions contain atleast one active ingredient that provides for observed therapeuticeffects. Among the active ingredients given in such antiinflammatorycompositions are indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, and nabumetone.

[0004] It is desirable to provide a new route of administration fornonsteroidal antiinflammatory drugs that rapidly produces peak plasmaconcentrations of the compounds. The provision of such a route is anobject of the present invention.

SUMMARY OF THE INVENTION

[0005] The present invention relates to the delivery of nonsteroidalanti-inflammatory drugs (NSAIDs) through an inhalation route.Specifically, it relates to aerosols containing NSAIDs that are used ininhalation therapy.

[0006] In a composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight of an NSAID.Preferably, the particles comprise at least 10 percent by weight of anNSAID. More preferably, the particles comprise at least 20 percent, 30percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97percent by weight of an NSAID.

[0007] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0008] Typically, the particles comprise less than 10 percent by weightof NSAID degradation products. Preferably, the particles comprise lessthan 5 percent by weight of NSAID degradation products. More preferably,the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent byweight of NSAID degradation products.

[0009] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0010] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0011] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

[0012] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0013] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.2.

[0014] Typically, the aerosol is formed by heating a compositioncontaining an NSAID to form a vapor and subsequently allowing the vaporto condense into an aerosol.

[0015] In another composition aspect of the present invention, theaerosol comprises particles comprising at least 5 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone. Preferably, the particles comprise at least10 percent by weight of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent or 99.97 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone.

[0016] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0017] Typically, the particles comprise less than 10 percent by weightof indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone degradation products. Preferably, theparticles comprise less than 5 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone degradation products. More preferably, the particles compriseless than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone degradation products.

[0018] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0019] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0020] Typically, the aerosol has an inhalable aerosol drug mass densitygreater than 5 mg/L. Preferably, the aerosol has an inhalable aerosoldrug mass density greater than 7.5 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density greater than 10 mg/L.

[0021] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

[0022] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0023] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.2.

[0024] Typically, the aerosol is formed by heating a compositioncontaining indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamicacid, fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone to form a vapor and subsequently allowingthe vapor to condense into an aerosol.

[0025] In a method aspect of the present invention, an NSAID isdelivered to a mammal through an inhalation route. The method comprises:a) heating a composition, wherein the composition comprises at least 5percent by weight of an NSAID, to form a vapor; and, b) allowing thevapor to cool, thereby forming a condensation aerosol comprisingparticles, which is inhaled by the mammal. Preferably, the compositionthat is heated comprises at least 10 percent by weight of an NSAID. Morepreferably, the composition comprises at least 20 percent, 30 percent,40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent,95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97percent by weight of an NSAID.

[0026] Typically, the particles comprise at least 5 percent by weight ofan NSAID. Preferably, the particles comprise at least 10 percent byweight of an NSAID. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of an NSAID.

[0027] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0028] Typically, the particles comprise less than 10 percent by weightof NSAID degradation products. Preferably, the particles comprise lessthan 5 percent by weight of NSAID degradation products. More preferably,the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight ofNSAID degradation products.

[0029] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0030] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0031] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0032] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.2.

[0033] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mLor 10⁸ particles/mL.

[0034] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhalable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhalable particles per second.

[0035] Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

[0036] Typically, the delivered condensation aerosol results in a peakplasma concentration of an NSAID in the mammal in less than 1 h.Preferably, the peak plasma concentration is reached in less than 0.5 h.More preferably, the peak plasma concentration is reached in less than0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

[0037] In another method aspect of the present invention, one ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone is delivered to a mammal through aninhalation route. The method comprises: a) heating a composition,wherein the composition comprises at least 5 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone, to form a vapor; and, b) allowing the vaporto cool, thereby forming a condensation aerosol comprising particles,which is inhaled by the mammal. Preferably, the composition that isheated comprises at least 10 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone. More preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetone.

[0038] Typically, the particles comprise at least 5 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone. Preferably, the particles comprise at least10 percent by weight of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone.

[0039] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0040] Typically, the particles comprise less than 10 percent by weightof indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone degradation products. Preferably, theparticles comprise less than 5 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone degradation products. More preferably, the particles comprise2.5, 1, 0.5, 0.1 or 0.03 percent by weight of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetonedegradation products.

[0041] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0042] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0043] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0044] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.2.

[0045] Typically, the delivered aerosol has an inhalable aerosol drugmass density greater than 5 mg/L. Preferably, the delivered aerosol hasan inhalable aerosol drug mass density greater than 7.5 mg/L. Morepreferably, the delivered aerosol has an inhalable aerosol drug massdensity greater than 10 mg/L.

[0046] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mLor 10⁸ particles/mL.

[0047] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhalable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhalable particles per second.

[0048] Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

[0049] Typically, greater than 5 mg of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetone isdelivered to the mammal in a single inspiration. Preferably, greaterthan 7.5 mg of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone is delivered to the mammal in asingle inspiration. More preferably, greater than 10 mg of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone is delivered to the mammal in a single inspiration.

[0050] Typically, the delivered condensation aerosol results in a peakplasma concentration of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone in the mammal in less than 1 h.Preferably, the peak plasma concentration is reached in less than 0.5 h.More preferably, the peak plasma concentration is reached in less than0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

[0051] In a kit aspect of the present invention, a kit for delivering anNSAID through an inhalation route to a mammal is provided whichcomprises: a) a composition comprising at least 5 percent by weight ofan NSAID; and, b) a device that forms an NSAID drug aerosol from thecomposition, for inhalation by the mammal. Preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of anNSAID.

[0052] Typically, the device contained in the kit comprises: a) anelement for heating the NSAID composition to form a vapor; b) an elementallowing the vapor to cool to form an aerosol; and, c) an elementpermitting the mammal to inhale the aerosol.

[0053] In a kit aspect of the present invention, a kit for deliveringindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone through an inhalation route to a mammal isprovided which comprises: a) a composition comprising at least 5 percentby weight of indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamicacid, fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone; and, b) a device that forms anindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone aerosol from the composition, for inhalationby the mammal. Preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetone.

[0054] Typically, the device contained in the kit comprises: a) anelement for heating the indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone composition to form a vapor; b)an element allowing the vapor to cool to form an aerosol; and, c) anelement permitting the mammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

[0055]FIG. 1 shows a cross-sectional view of a device used to deliverNSAID aerosols to a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

[0056] Definitions

[0057] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0058] “Aerosol” refers to a suspension of solid or liquid particles ina gas.

[0059] “Aerosol drug mass density” refers to the mass of NSAID per unitvolume of aerosol.

[0060] “Aerosol mass density” refers to the mass of particulate matterper unit volume of aerosol.

[0061] “Aerosol particle density” refers to the number of particles perunit volume of aerosol.

[0062] “Amorphous particle” refers to a particle that does not containmore than 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

[0063] “Celecoxib” refers to4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

[0064] “Celecoxib degradation product” refers to a compound resultingfrom a chemical modification of celecoxib. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0065] “Condensation aerosol” refers to an aerosol formed byvaporization of a substance followed by condensation of the substanceinto an aerosol.

[0066] “Diflunisal” refers to2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxylic acid.

[0067] “Diflunisal degradation product” refers to a compound resultingfrom a chemical modification of diflunisal. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0068] “Fenoprofen” refers to α-methyl-3-phenoxy-benzeneacetic acid.

[0069] “Fenoprofen degradation product” refers to a compound resultingfrom a chemical modification of fenoprofen. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0070] “Flurbiprofen” refers to2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid.

[0071] “Flurbiprofen degradation product” refers to a compound resultingfrom a chemical modification of flurbiprofen. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0072] “Ibuprofen” refers to α-methyl-4-(2-methyl-propyl)benzene aceticacid.

[0073] “Ibuprofen degradation product” refers to a compound resultingfrom a chemical modification of ibuprofen. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0074] “Indomethacin” refers to1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid.

[0075] “Indomethacin degradation product” refers to a compound resultingfrom a chemical modification of indomethacin. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0076] “Inhalable aerosol drug mass density” refers to the aerosol drugmass density produced by an inhalation device and delivered into atypical patient tidal volume.

[0077] “Inhalable aerosol mass density” refers to the aerosol massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

[0078] “Inhalable aerosol particle density” refers to the aerosolparticle density of particles of size between 100 nm and 5 micronsproduced by an inhalation device and delivered into a typical patienttidal volume.

[0079] “Ketoprofen” refers to 3-benzoyl-α-methyl-benzeneacetic acid.

[0080] “Ketoprofen degradation product” refers to a compound resultingfrom a chemical modification of ketoprofen. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0081] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0082] “Meclofenamic Acid” refers to2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid.

[0083] “Meclofenamic acid degradation product” refers to a compoundresulting from a chemical modification of meclofenamic acid. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0084] “Nabumetone” refers to 4-(6-methoxy-2-naphthalenyl)-2-butanone.

[0085] “Nabumetone degradation product” refers to a compound resultingfrom a chemical modification of nabumetone. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0086] “Naproxen” refers to (αS)-6-methoxy-α-methyl-2-naphthaleneaceticacid.

[0087] “Naproxen degradation product” refers to a compound resultingfrom a chemical modification of naproxen. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

[0088] “NSAID degradation product” refers to a compound resulting from achemical modification of an NSAID. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

[0089] “Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

[0090] “Rate of inhalable aerosol particle formation” refers to thenumber of particles of size between 100 nm and 5 microns produced by aninhalation device per unit time.

[0091] “Rate of drug aerosol formation” refers to the mass ofaerosolized NSAID produced by an inhalation device per unit time.

[0092] “Rofecoxib” refers to4-[4-(methylsulfonyl)-phenyl]-3-phenyl-2(5H)-furanone.

[0093] “Rofecoxib degradation product” refers to a compound resultingfrom a chemical modification of rofecoxib. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0094] “Tolfenamic acid” refers to2-[(3-chloro-2-methylphenyl)amino]benzoic acid.

[0095] “Tolfenamic acid degradation product” refers to a compoundresulting from a chemical modification of tolfenamic acid. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0096] “Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

[0097] “Typical patient tidal volume” refers to 1 L for an adult patientand 15 mL/kg for a pediatric patient.

[0098] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.The term “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

[0099] Formation of NSAID Containing Aerosols

[0100] Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising an NSAID to form a vapor, followed by cooling of the vaporsuch that it condenses to provide an NSAID comprising aerosol(condensation aerosol). The composition is heated in one of four forms:as pure active compound (e.g., pure indomethacin, ketoprofen, celcoxib,rofecoxib, meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid,naproxen, ibuprofen, flurbiprofen, or nabumetone); as a mixture ofactive compound and a pharmaceutically acceptable excipient; as a saltform of the pure active compound; and, as a mixture of active compoundsalt form and a pharmaceutically acceptable excipient.

[0101] Salt forms of NSAIDs (e.g., indomethacin, ketoprofen, celcoxib,rofecoxib, meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid,naproxen, ibuprofen, flurbiprofen, or nabumetone) are eithercommercially available or are obtained from the corresponding free baseusing well known methods in the art. A variety of pharmaceuticallyacceptable salts are suitable for aerosolization. Such salts include,without limitation, the following: hydrochloric acid, hydrobromic acid,acetic acid, maleic acid, formic acid, and fumaric acid salts.

[0102] Pharmaceutically acceptable excipients may be volatile ornonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with the NSAID. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

[0103] Solid supports on which the composition is heated are of avariety of shapes. Examples of such shapes include, without limitation,cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mmthickness and virtually any shape permeated by small (e.g., less than1.0 mm-sized) pores. Preferably, solid supports provide a large surfaceto volume ratio (e.g., greater than 100 per meter) and a large surfaceto mass ratio (e.g., greater than 1 cm² per gram).

[0104] A solid support of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0105] A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

[0106] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Carbon yarns and felts are available fromAmerican Kynol, Inc., New York, N.Y. Chromatography resins such asoctadecycl silane chemically bonded to porous silica are exemplarycoated variants of silica.

[0107] The heating of the NSAID compositions is performed using anysuitable method. Examples of methods by which heat can be generatedinclude the following: passage of current through an electricalresistance element; absorption of electromagnetic radiation, such asmicrowave or laser light; and, exothermic chemical reactions, such asexothermic solvation, hydration of pyrophoric materials and oxidation ofcombustible materials.

[0108] Delivery of NSAID Containing Aerosols

[0109] NSAID containing aerosols of the present invention are deliveredto a mammal using an inhalation device. Where the aerosol is acondensation aerosol, the device has at least three elements: an elementfor heating an NSAID containing composition to form a vapor; an elementallowing the vapor to cool, thereby providing a condensation aerosol;and, an element permitting the mammal to inhale the aerosol. Varioussuitable heating methods are described above. The element that allowscooling is, in it simplest form, an inert passageway linking the heatingmeans to the inhalation means. The element permitting inhalation is anaerosol exit portal that forms a connection between the cooling elementand the mammal's respiratory system.

[0110] One device used to deliver the NSAID containing aerosol isdescribed in reference to FIG. 1. Delivery device 100 has a proximal end102 and a distal end 104, a heating module 106, a power source 108, anda mouthpiece 110. An NSAID composition is deposited on a surface 112 ofheating module 106. Upon activation of a user activated switch 114,power source 108 initiates heating of heating module 106 (e.g, throughignition of combustible fuel or passage of current through a resistiveheating element). The NSAID composition volatilizes due to the heatingof heating module 106 and condenses to form a condensation aerosol priorto reaching the mouthpiece 110 at the proximal end of the device 102.Air flow traveling from the device distal end 104 to the mouthpiece 110carries the condensation aerosol to the mouthpiece 110, where it isinhaled by the mammal.

[0111] Devices, if desired, contain a variety of components tofacilitate the delivery of NSAID containing aerosols. For instance, thedevice may include any component known in the art to control the timingof drug aerosolization relative to inhalation (e.g., breath-actuation),to provide feedback to patients on the rate and/or volume of inhalation,to prevent excessive use (i.e., “lock-out” feature), to prevent use byunauthorized individuals, and/or to record dosing histories.

[0112] Dosage of NSAID Containing Aerosols

[0113] The dosage amount of an NSAID in aerosol form is generally nogreater than twice the standard dose of the drug given orally;oftentimes, the dose is less than the standard oral dose. (Indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone are typically provided at the following strengths for oraladministration: 25 mg, 25 to 50 mg, 100 mg, 50 mg, 200 mg, 50 mg, 200mg, 250 mg, 200 mg, 250 mg, 200 mg, 50 mg, and 500 mg respectively.) Atypical dosage of an NSAID aerosol is either administered as a singleinhalation or as a series of inhalations taken within an hour or less(dosage equals sum of inhaled amounts). Where the drug is administeredas a series of inhalations, a different amount may be delivered in eachinhalation.

[0114] One can determine the appropriate dose of NSAID containingaerosols to treat a particular condition using methods such as animalexperiments and a dose-finding (Phase I/II) clinical trial. One animalexperiment involves measuring plasma concentrations of drug in an animalafter its exposure to the aerosol. Mammals such as dogs or primates aretypically used in such studies, since their respiratory systems aresimilar to that of a human. Initial dose levels for testing in humans isgenerally less than or equal to the dose in the mammal model thatresulted in plasma drug levels associated with a therapeutic effect inhumans. Dose escalation in humans is then performed, until either anoptimal therapeutic response is obtained or a dose-limiting toxicity isencountered.

[0115] Analysis of NSAID Containing Aerosols

[0116] Purity of an NSAID containing aerosol is determined using anumber of methods, examples of which are described in Sekine et al.,Journal of Forensic Science 32:1271-1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158-162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

[0117] A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

[0118] The gas or liquid chromatograph discussed above contains adetection system (i.e., detector). Such detection systems are well knownin the art and include, for example, flame ionization, photon absorptionand mass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure of NSAIDdegradation products.

[0119] Particle size distribution of an NSAID containing aerosol isdetermined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

[0120] Inhalable aerosol mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0121] Inhalable aerosol drug mass density is determined, for example,by delivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

[0122] Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*(φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

[0123] Rate of inhalable aerosol particle formation is determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

[0124] Rate of aerosol formation is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice. The delivery is for a set period of time (e.g., 3 s), and themass of particulate matter collected is determined by weighing theconfined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0125] Rate of drug aerosol formation is determined, for example, bydelivering an NSAID containing aerosol into a confined chamber via aninhalation device over a set period of time (e.g., 3 s). Where theaerosol is pure NSAID, the amount of drug collected in the chamber ismeasured as described above. The rate of drug aerosol formation is equalto the amount of NSAID collected in the chamber divided by the durationof the collection time. Where the NSAID containing aerosol comprises apharmaceutically acceptable excipient, multiplying the rate of aerosolformation by the percentage of NSAID in the aerosol provides the rate ofdrug aerosol formation.

[0126] Utility of NSAID Containing Aerosols

[0127] The NSAID containing aerosols of the present invention aretypically used for the treatment of inflammation.

[0128] The following examples are meant to illustrate, rather thanlimit, the present invention.

[0129] Indomethacin, ketoprofen, meclofenamic acid sodium salt,fenoprofen calcium salt, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, and nabumetone are commercially available fromSIGMA (www.sigma-aldrich.com). Celecoxib and rofecoxib can be isolatedusing standard methods from CELEBREX® and VIOXX® respectively. OtherNSAIDs can be similarly obtained.

EXAMPLE 1 General Procedure for Volatilizing Compounds

[0130] A solution of drug in a minimal amount of an appropriate solvent(e.g., dichloromethane or methanol) is coated on a 4.0 cm×7.5 cm pieceof aluminum foil (precleaned with acetone). The solvent is allowed toevaporate. The coated foil is wrapped around a 300 watt halogen tube(Feit Electric Company, Pico Rivera, Calif.), which is inserted into aglass tube sealed at one end with a rubber stopper. Running 60 V ofalternating current (driven by line power controlled by a variac)through the bulb for 3-18 s affords thermal vapor (including aerosol),which is collected on the glass tube walls. Reverse-phase HPLC analysiswith detection by absorption of 225 nm light is used to determine thepurity of the aerosol. (When desired, the system is flushed through withargon prior to volatilization.)

[0131] NSAID aerosols were obtained in the following purities andamounts using this procedure: indomethacin (99% purity, 0.61 mg);ketoprofen (100% purity, 2.72 mg); celecoxib (100% purity, 10 mg);rofecoxib (97.5% purity, 4.1 mg); meclofenamic acid (100% purity);fenoprofen (100%, 1.61 mg); diflunisal (100%, 5.47 mg); tolfenamic acid(94.2% purity, 6.49 mg); naproxen (100% purity, 4 mg); ibuprofen (100%purity, 1.81 mg); flurbiprofen (100% purity, 4.1 mg); and, nabumetone(100% purity, 4.8 mg).

1. A method of treating inflammation comprising administering atherapeutic amount of a nonsteroidal anti-inflammatory drug condensationaerosol, having an MMAD less than 3 μm and less than 5% nonsteroidalanti-inflammatory drug degradation products, to a patient by inhalation,upon activation by the patient of the formation of, and delivery of, thecondensation aerosol.
 2. The method of claim 1, wherein saidcondensation aerosol is formed by a. volatilizing a nonsteroidalanti-inflammatory drug under conditions effective to produce a heatedvapor of the nonsteroidal anti-inflammatory drug; and b. condensing theheated vapor of the nonsteroidal anti-inflammatory drug to formcondensation aerosol particles.
 3. The method according to claim 2,wherein said administration results in a peak plasma concentration ofsaid nonsteroidal anti-inflammatory drug in less than 0.1 hours.
 4. Themethod of claim 2, wherein the nonsteroidal anti-inflammatory drug isselected from the group consisting of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetone. 5.The method according to claim 1, wherein the administered aerosol isformed at a rate greater than 0.5 mg/second.
 6. The method according toclaim 1, wherein at least 50% by weight of the condensation aerosol isamorphous in form.
 7. A method of treating inflammation comprisingadministering a therapeutic amount of an indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetonecondensation aerosol, having an MMAD less than 3 μm and less than 5%indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone degradation products, to a patient byinhalation, upon activation by the patient of the formation of, anddelivery of, the condensation aerosol.
 8. The method of claim 7, whereinsaid condensation aerosol is formed by a. volatilizing indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone under conditions effective to produce a heated vapor ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone; and b. condensing the heated vapor ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone to form condensation aerosol particles. 9.The method according to claim 8, wherein said administration results ina peak plasma concentration of said indomethacin, ketoprofen, celcoxib,rofecoxib, meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid,naproxen, ibuprofen, flurbiprofen, or nabumetone in less than 0.1 hours.10. The method according to claim 7, wherein at least 50% by weight ofthe condensation aerosol is amorphous in form.
 11. The method accordingto claim 7, wherein said condensation aerosol has an inhalable aerosolmass density greater than 5 mg/L when delivered.
 12. The methodaccording to claim 7, wherein said condensation aerosol has an inhalableaerosol mass density greater than 7.5 mg/L when delivered.
 13. Themethod according to claim 7, wherein said condensation aerosol has aninhalable aerosol mass density greater than 10 mg/L when delivered. 14.A method of administering a nonsteroidal antiinflammatory drug to apatient to achieve a peak plasma drug concentration rapidly, comprisingadministering to the patient by inhalation an aerosol of a nonsteroidalanti-inflammatory drug having less than 5% nonsteroidal antiinflammatorydrug degradation products and an MMAD less than 3 microns wherein thepeak plasma drug concentration of the nonsteroidal anti-inflammatorydrug is achieved in less than 0.1 hours.
 15. A method of administeringindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone to a patient to achieve a peak plasma drugconcentration rapidly, comprising administering to the patient byinhalation an aerosol of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone having less than 5% indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone degradation products and an MMAD less than 3 microns whereinthe peak plasma drug concentration of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetone isachieved in less than 0.1 hours.
 16. A kit for delivering a drug aerosolcomprising: a) a thin coating of a nonsteroidal antiinflammatory drugcomposition and b) a device for dispensing said thin coating as acondensation aerosol.
 17. The kit of claim 16, wherein the nonsteroidalantiinflammatory drug of the composition is selected from the groupconsisting of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone
 18. The kit of claim 16, whereinthe device for dispensing said coating of a nonsteroidalantiinflammatory drug composition as an aerosol comprises (a) a flowthrough enclosure, (b) contained within the enclosure, a metal substratewith a foil-like surface and having a thin coating of a nonsteroidalantiinflammatory drug composition formed on the substrate surface, (c) apower source that can be activated to heat the substrate to atemperature effective to volatilize the nonsteroidal antiinflammatorydrug composition contained in said coating, and (d) inlet and exitportals through which air can be drawn through said device byinhalation, wherein heating the substrate by activation of the powersource is effective to form a nonsteroidal antiinflammatory drug vaporcontaining less than 5% nonsteroidal antiinflammatory drug degradationproducts, and drawing air through said chamber is effective to condensethe nonsteroidal antiinflammatory drug vapor to form aerosol particleswherein the aerosol has an MMAD of less than 3 microns.
 19. The kitaccording to claim 18, wherein the heat for heating the substrate isgenerated by an exothermic chemical reaction.
 20. The kit according toclaim 19, wherein said exothermic chemical reaction is oxidation ofcombustible materials.
 21. The kit according to claim 18, wherein theheat for heating the substrate is generated by passage of currentthrough an electrical resistance element.
 22. The kit according to claim18, wherein said substrate has a surface area dimensioned to accommodatea therapeutic dose of a nonsteroidal antiinflammatory drug compositionin said coating.
 23. The kit according to claim 16, wherein a peakplasma concentration of anonsteroidal antiinflammatory drug is obtainedin less than 0.1 hours after delivery of the condensation aerosol to thepulmonary system.
 24. The kit of claim 16, further includinginstructions for use.